OBJECTIVE: Gastric cancer (GC) is one of the most common malignancies seen in clinic and requires novel treatment options. Morin is a natural flavonoid extracted from the flower stalk of a highly valuable medicinal plant Prunella vulgaris L., which exhibits an anti-cancer effect in multiple types of tumors. However, the therapeutic effect and underlying mechanism of morin in treating GC remains elusive. The study aims to explore the therapeutic effect and underlying molecular mechanisms of morin in GC. METHODS: For in vitro experiments, the proliferation inhibition of morin was measured by cell counting kit-8 assay and colony formation assay in human GC cell line MKN45, human gastric adenocarcinoma cell line AGS, and human gastric epithelial cell line GES-1; for apoptosis analysis, microscopic photography, Western blotting, ubiquitination analysis, quantitative polymerase chain reaction analysis, flow cytometry, and RNA interference technology were employed. For in vivo studies, immunohistochemistry, biomedical analysis, and Western blotting were used to assess the efficacy and safety of morin in a xenograft mouse model of GC. RESULTS: Morin significantly inhibited the proliferation of GC cells MKN45 and AGS in a dose- and time-dependent manner, but did not inhibit human gastric epithelial cells GES-1. Only the caspase inhibitor Z-VAD-FMK was able to significantly reverse the inhibition of proliferation by morin in both GC cells, suggesting that apoptosis was the main type of cell death during the treatment. Morin induced intrinsic apoptosis in a dose-dependent manner in GC cells, which mainly relied on B cell leukemia/lymphoma 2 (BCL-2) associated agonist of cell death (BAD) but not phorbol-12-myristate-13-acetate-induced protein 1. The upregulation of BAD by morin was due to blocking the ubiquitination degradation of BAD, rather than the transcription regulation and the phosphorylation of BAD. Furthermore, the combination of morin and BCL-2 inhibitor navitoclax (also known as ABT-737) produced a synergistic inhibitory effect in GC cells through amplifying apoptotic signals. In addition, morin treatment significantly suppressed the growth of GC in vivo by upregulating BAD and the subsequent activation of its downstream apoptosis pathway. CONCLUSION Morin suppressed GC by inducing apoptosis, which was mainly due to blocking the ubiquitination-based degradation of the pro-apoptotic protein BAD. The combination of morin and the BCL-2 inhibitor ABT-737 synergistically amplified apoptotic signals in GC cells, which may overcome the drug resistance of the BCL-2 inhibitor. These findings indicated that morin was a potent and promising agent for GC treatment. Please cite this article as: Wang Y, Sun XY, Ma FQ, Ren MM, Zhao RH, Qin MM, Zhu XH, Xu Y, Cao ND, Chen YY, Dong TG, Pan YF, Zhao AG. Morin inhibits ubiquitination degradation of BCL-2 associated agonist of cell death and synergizes with BCL-2 inhibitor in gastric cancer cells. J Integr Med. 2025; 23(3): 320-332.
Humans ; Flavonoids/therapeutic use* ; Stomach Neoplasms/pathology* ; Animals ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Cell Line, Tumor ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Ubiquitination/drug effects* ; Mice ; Drug Synergism ; Mice, Inbred BALB C ; Mice, Nude ; Xenograft Model Antitumor Assays ; Flavones

Background::Although overnight fasting is recommended prior to endoscopic retrograde cholangiopancreatography (ERCP), the benefits and safety of high-carbohydrate fluid diet (CFD) intake 2 h before ERCP remain unclear. This study aimed to analyze whether high-CFD intake 2 h before ERCP can be safe and accelerate patients’ recovery.Methods::This prospective, multicenter, randomized controlled trial involved 15 tertiary ERCP centers. A total of 1330 patients were randomized into CFD group ( n = 665) and fasting group ( n = 665). The CFD group received 400 mL of maltodextrin orally 2 h before ERCP, while the control group abstained from food/water overnight (>6 h) before ERCP. All ERCP procedures were performed using deep sedation with intravenous propofol. The investigators were blinded but not the patients. The primary outcomes included postoperative fatigue and abdominal pain score, and the secondary outcomes included complications and changes in metabolic indicators. The outcomes were analyzed according to a modified intention-to-treat principle. Results::The post-ERCP fatigue scores were significantly lower at 4 h (4.1 ± 2.6 vs. 4.8 ± 2.8, t = 4.23, P <0.001) and 20 h (2.4 ± 2.1 vs. 3.4 ± 2.4, t= 7.94, P <0.001) in the CFD group, with least-squares mean differences of 0.48 (95% confidence interval [CI]: 0.26–0.71, P <0.001) and 0.76 (95% CI: 0.57–0.95, P <0.001), respectively. The 4-h pain scores (2.1 ± 1.7 vs. 2.2 ± 1.7, t = 2.60, P = 0.009, with a least-squares mean difference of 0.21 [95% CI: 0.05–0.37]) and positive urine ketone levels (7.7% [39/509] vs. 15.4% [82/533], χ2 = 15.13, P <0.001) were lower in the CFD group. The CFD group had significantly less cholangitis (2.1% [13/634] vs. 4.0% [26/658], χ2 = 3.99, P = 0.046) but not pancreatitis (5.5% [35/634] vs. 6.5% [43/658], χ2 = 0.59, P = 0.444). Subgroup analysis revealed that CFD reduced the incidence of complications in patients with native papilla (odds ratio [OR]: 0.61, 95% CI: 0.39–0.95, P = 0.028) in the multivariable models. Conclusion::Ingesting 400 mL of CFD 2 h before ERCP is safe, with a reduction in post-ERCP fatigue, abdominal pain, and cholangitis during recovery.Trail Registration::ClinicalTrials.gov, No. NCT03075280.

Objective:To systematically summarize and comparatively analyze the development, establishment and usage of oncology drugs speedy review approaches in China and in the United States between 2012 and 2021.Methods:Based on National Medical Products Administration (NMPA) and Food and Drug Administration (FDA) websites, the development and current status of the speedy review approaches were consulted and summarized. Approved oncology drugs in China and in the United States (87 in China, 118 in the United States) over the past decade were analyzed using chi-square test for group comparison.Results:Five speedy approaches have been established in China and in the United States, three of which are the same, priority review, conditional approval or accelerated approval and breakthrough therapy. The rest two are special review and approval, special examination and approval in China, and fast track and real-time oncology review in the United States. Compared to the United States, speedy review approaches in China set up late (1992 vs. 2005). The overall utilization rates of the oncology drugs speedy review approaches were similar between the China and United States (90.8% vs. 92.4%, P=0.800) in the previous 10 years, and priority review have highest utilization rates in both China and the United States without significant group difference (77.0% vs. 82.2%, P=0.381); relatively low utilization rates of conditional approval (31.0% vs. 44.9%, P=0.041) and breakthrough therapy (2.3% vs. 50.0%, P＜0.001) were seen in China. 52.9% of new drugs applied for special examination and approval in China and 40.7% of new drugs applied for fast track in the United States. Overall, the priority review both in China and the United States are stable, with a similar average annual utilization rate (84.8% vs. 83.7%); accelerated approval and breakthrough therapies in the United States fluctuate wildly, but the situation is tending towards stability in the last 3 years. Conclusions:Both China and the United States have established a relatively complete accelerated review system, with an overall utilization rate over 90%; China's accelerated review started late, although the overall utilization rate is close to that of the United States. The utilization rates of conditional approval and breakthrough therapy are still relatively low. Flexible usage of speedy review approaches, gaining regulatory recognition to use alternative endpoints, achieving real-time review and guidance are keys to accelerate new drug development in China.

Objective To explore the effect and mechanism of hydroxysafflor yellow A(HSYA)on autophagy in bEnd.3 cells after oxygen-glucose deprivation(OGD).Methods The bEnd.3 cells were divided into normal group(conventional culture),model group(OGD model),HSYA group(OGD model+75 μmol·L-1 HSYA),3-methyladenine(3MA)group(5 mmol·L-1 3MA+OGD model)and 3 MA+HSYA group(5 mmol·L-1 3 MA+OGD model+75 μmol·L-1 HSYA).The level of apoptosis was determined by TUNEL fluorescence staining;Western blot was used to detect the expression of autophagy,blood brain barrier(BBB)related proteins;real time fluorescence quantitative polymerase chain reaction method for determining the expression of sirtuin-1(SIRT1)and forkhead box protein O3a(FOXO3A)mRNA.Results In the normal group,model group,HSYA group,3MA group and 3MA+HSYA group,the positive cells selected for TUNEL staining were 5.00±1.00,28.00±2.00,21.00±3.00,35.33±2.51 and 29.67±2.52;the expression levels of microtubule-associated protein 1 light chain 3-Ⅱ/-Ⅰ(LC3-Ⅱ/-Ⅰ)were 0.90±0.20,1.34±0.10,1.95±0.14,0.76±0.15 and 1.14±0.09;sequestosome 1(P62)were 0.99±0.02,0.60±0.02,0.38±0.01,0.67±0.04 and 0.54±0.01;occludin were 1.39±0.17,0.62±0.15,1.00±0.09,0.40±0.13 and 0.80±0.15;zonula occludens-1(ZO-1)were 1.63±0.20,0.64±0.06,0.98±0.14,0.37±0.14 and 0.87±0.04;SIRT1 mRNA were 1.00±0.00,0.75±0.07,1.69±0.09,0.31±0.02 and 0.56±0.01;FOXO3A mRNA were 1.00±0.00,0.80±0.05,1.47±0.09,0.40±0.01 and 0.62±0.09,respectively.Significant differences were found between model group and normal group,HSYA group and model group,3MA+HSYA group and 3MA group(P＜0.05,P＜0.01,P＜0.001).Conclusion HSYA may enhance autophagy levels in bEnd.3 cells after OGD through the SIRT1/FOXO3A pathway,inhibit cell apoptosis and alleviate BBB damage.

BackgroundThe development of executive function in adolescents is influenced by many environmental factors. Previous studies have found that perceived stress is closely related to executive function， whereas its role in the mediation of executive function remains poorly studied. ObjectiveTo explore the role of negative affect and self-hate in mediating the relationship between perceived stress and executive function in adolescents， so as to assist the improvement of executive function in adolescents. MethodsQuestionnaires were administered to 7 734 adolescents from five junior and five senior high schools in Rizhao city， Shandong province from 1 to 30 May 2022. Data were collected using a self-made questionnaire， and adolescents were assessed using Perceived Stress Scale （PSS）， Behavior Rating Inventory of Executive Function-Self Report Version （BRIEF-SR）， Patient Health Questionnaire （PHQ-4） and Self-Hate Scale （SHS）. Spearman correlation analysis was conducted to examine the correlation between variables. A Bootstrap method was chosen to examine the mediation effect of self-hate and negative affect on the relationship between perceived stress and executive function in adolescents. ResultsA total of 7 012 （90.66%） valid questionnaires were retrieved. BRIEF-SR score was positively correlated with PSS， PHQ-4 and SHS scores （r=0.564， 0.653， 0.597， P<0.01）. PSS score was positively correlated with PHQ-4 and SHS scores （r=0.615， 0.531， P<0.01）. PHQ-4 score was positively correlated with SHS score （r=0.566， P<0.01）. The value of mediation effect of perceived stress on executive function was 0.574 （95% CI： 0.555~0.594）. Self-hate （indirect effect value of 0.160， 95% CI： 0.145~0.175） and negative affect （indirect effect value of 0.143， 95% CI： 0.129~0.158）， separately from each other， mediated the relationship between perceived stress and executive function， and a chained mediation effect of self-hate and negative affect was also documented （indirect effect value of 0.065， 95% CI： 0.058~0.073）， accounting for 27.87%， 24.91% and 11.32% of the total effect， respectively. ConclusionThe perceived stress of adolescents may be a influencing factor of the executive function. Additionally， perceived stress can either directly affect executive function or indirectly through the separate or chained mediation via negative affect and self-hate.

Six compounds were isolated from the roots of Ephedra sinica Stapf using various chromatographic techniques such as silica gel column chromatography, thin layer chromatography and semi-preparative HPLC. Their chemical structures were identified by analysis of physicochemical properties and spectral data, and determined as (Z)-docosanylferulate (1), (E)-docosanylferulate (2), bis (2-ethylheptyl) phythalate (3), 2,2′-oxybis (1,4-di-tert-butylbenzene) (4), diisobutyl phthalate (5), bis (2-ethylhexyl) phthalate (6). Among them, compound 1 is a new compound, compounds 2-4 were first isolated from Ephedra. A corticosterone-induced PC-12 cell injury model was used for compound activity screening. The results showed that compounds 1 and 5 significantly improved corticosterone-induced PC-12 cell injury and significantly increased 5-HT₇ receptor protein expression in the cells, indicating potential antidepressant activity.

Objective:To investigate associations between cardiac biomarkers with stroke severity and short-term outcome in patients with acute ischemic stroke (AIS).Methods:Patients with AIS admitted to the Affiliated Hospital of Qingdao University from June 2018 to February 2024 whose etiological classification was large artery atherosclerosis (LAA), small vessel occlusion (SVO) or cardioembolism (CE) were included retrospectively. According to the National Institutes of Health Stroke Scale score at admission, patients were divided into mild stroke group (≤8) and moderate to severe stroke group (>8). According to the modified Rankin Scale score at discharge, patients were divided into good outcome group (≤2) and poor outcome group (>2). Multivariate logistic regression analysis was used to determine the independent correlation between cardiac biomarkers and short-term outcome. The predictive value of cardiac biomarkers for poor outcome in patients with AIS and different stroke etiology subtypes were evaluated using receiver operating characteristic (ROC) curves. Results:A total of 2 151 patients with AIS were enrolled, including 1 256 males (58.4%), aged 67.40±11.34 years. 1 079 patents were LAA type (50.2%), 679 were SVO type (31.6%), and 393 were CE type (18.3%); 1 223 were mild stroke (56.86%) and 928 (43.14%) were moderate to severe stroke; 1 357 patients (63.09%) had good short-term outcome, and 794 (36.91%) had poor short-term outcome. Multivariate logistic regression analysis showed that N-terminal pro-B type natriuretic peptide (NT-proBNP), NT-proBNP/creatine kinase (CK) isoenzyme MB (CK-MB) ratio, and CK-MB/CK ratio were independent risk factors for poor short-term outcome. ROC curve analysis shows that the CK-MB/CK ratio had a higher predictive value for short-term poor outcome in patients with AIS (the area under the curve, 0.859, 95% confidence interval 0.839-0.879). Various cardiac biomarkers had a higher predictive value for short-term outcome of CE type and LAA type, but the predictive value for short-term outcome of SVO type was lower. Conclusions:Cardiac biomarkers are associated with the severity and poor outcome of AIS. NT-proBNP/CK-MB and CK-MB/CK ratios have higher predictive value for short-term poor outcome of AIS, especially in patients with CE type.

Objective To analyze the influence of medication compliance of chronic type 2 diabetes management patients on disease control in two communities in Kunming.Methods A total of 138 patients with type 2 diabetes who were included in chronic disease management in Guandu and Xiaobanqiao communities of Kunming were selected from December 2021 to September 2022.Basic information collection and HbAlc and other related tests were improved.A questionnaire survey of 8-item Morisliy medication adherence scale(MMAS-8)was conducted to analyze the levels of HbAlc and other indexes of three groups with high(group A),medium(group B),and low(group C)adherence,and to conduct statistical analysis.Results Group A accounted for 22.5%,group B for 44.9%,and group C for 32.6%.There were significance differences in urinary albumin creatinine ratio(UACR),HbA1c and blood creatinine among the three groups(P<0.05).The levels of UACR,HbAlc and serum creatinine in group A were lower than those in group B and group C,and there was a negative correlation between UACR,HbAlc and serum creatinine and medication compliance rate(P<0.05).Conclusion In the Guandu Community and Xiaobanqiao community of Kunming,only 22.5%of patients with chronic type 2 diabetes had high medication compliance.The higher the compliance,the lower the level of UACR,HbAlc and serum creatinine,there is a correlation between the two,suggesting that medication compliance should be regarded as one of the key points in the management of chronic diabetes mellitus in the community,and the intervention of patients'medication compliance should be strengthened.

Tricuspid regurgitation(TR)is a common heart valve disease.According to the pathogenesis,TR can be divided into primary(organic)and secondary(functional)regurgitation,of which functional TR accounts for more than 90%.Patients with severe TR have poor prognosis and poor drug treatment,and surgery(valvuloplasty)is the main treatment.At present,transcatheter edge-to-edge tricuspid valve repair(T-TEER)has become an essential program of transcatheter treatment for TR,providing minimally invasive treatment for TR patients who cannot undergo surgery or are at high risk of surgery.T-TEER reduces the degree of regurgitation by clamping leaflets,and is currently in the early stage of research and development exploration and clinical validation,mainly for functional TR.T-TEER devices have also made significant progress(TriClip,PASCAL),and Chinese-made novel-designed T-TEER devices are also undergoing clinical trials(DragonFly-TTM,SQ-Kyrin-TTM,NeoBlazarTM).This paper reviews the current applications and research progress of T-TEER.

To understand Helicobacter pylori's drug resistance,genetic diversity,and relationship with clinical diseases in the Guiyang and Qiannan minority areas of Guizhou Province,we collected samples through endoscopy,and isolated and cul-tured H.pylori.The drug resistance and genotype characteristics were determined.The differences in different regions and dis-ease types were compared,and the structural characteristics of H.pylori and mixed infections with different strains of H.py-lori in Qiannan Prefecture were analyzed.A difference in the composition ratio of EPYIA typing in the cagA variable region was observed between the two areas(P=0.012),and the composition ratio of the vacA genotype differed(P=0.000).A total of 94.6％(53/56)new sequences of H.pylori strains from two regions were obtained by MLST.The rate of infection by H.pylori mixed with different strains was 44.4％in Qiannan Pre-fecture,and no significant difference was observed in the com-position of H.pylori mixed infections among patients with dif-ferent clinical diseases(P=0.349).Differences in EPI YA typ-ing and the vacA genotype composition ratio in the cagA varia-ble region of H.pylori were observed between the Qiannan Prefecture and Guiyang City.